PROJECT SUMMARY The current US ?opioid crisis? fueled by over 225 million annual prescriptions of mu-opioid receptor (MOR) agonist analgesics and characterized by unprecedented levels of addiction, abuse and death by overdose, has emphasized the need for novel, efficacious, non-addictive and safe analgesics. The proposed program seeks to develop a first-in-class (FIC), peripherally-restricted and long-acting MAS1 (LA-MAS1) agonist with potential to reduce or replace MOR agonists for moderate-to-severe pain, and that will be non-addictive, safe and convenient to use. The program is based on strong scientific evidence showing that activation of MAS1, a peptidic G protein- coupled receptor (GPCR), produces opioid-independent and peripheral antinociceptive activity in a wide range of animal models of chronic pain, including inflammatory, neuropathic and bone cancer pain. We propose to conjugate existing short-acting peptidic MAS1 agonists to CVX-2000, a ?plug and play? and re-usable antibody carrier, previously clinically-validated for extending the half-life of peptides, and successfully used by us to create other long-acting peripheral analgesics (LPAs), including long-acting kappa-opioid receptor (LA-KOR) agonists and long-acting somatostatin receptor type 4 (LA-SSTR4) agonists. The resulting LA-MAS1 peptide-antibody conjugates (PACs) will retain potent agonistic activity and selectivity at MAS1 while acquiring the pharmaco- kinetic (PK) properties of the antibody carrier, thereby achieving both (i) long elimination half-life and (ii) high peripheral selectivity. These two key features will provide LA-MAS1 agonists with a highly differentiated and superior target product profile (TPP) in terms of efficacy, safety and convenience compared to short-acting and brain-penetrating small molecule analgesics currently in development. The extended half-life will enable less frequent, simpler and more convenient administration, i.e., once-weekly or twice-monthly subcutaneous dosing that in turn will improve compliance while ensuring continuous drug exposure at effective plasma concentration, which combined, will maximize efficacy. The lack of penetration in the central nervous system (CNS) will prevent unnecessary and undesired interaction with the widely distributed MAS1 in the CNS, thereby eliminating any risk of CNS-mediated MAS1 adverse effects. Finally, unlike MOR agonists, LA-MAS1 agonists will not induce respiratory depression, nausea, vomiting, itching, constipation, drowsiness, mental cloudiness, dependence, addiction or abuse. The current SBIR Phase I program aims to assess the chemical feasibility of creating potent, selective and stable LA-MAS1 agonists. The subsequent Phase II program will include further lead optimization, evaluation of efficacy, potency and duration of action in animal pain models, preclinical PK studies and selection of a clinical candidate new biological entity (NBE) for nonclinical development. IMPACT & Relevance to Public Health: This program has potential to bring forward novel, efficacious, non-addictive, safe and convenient analgesics able to reduce or replace opioids for the treatment of moderate-to-severe pain, thus improving pain control while maintaining patient safety and quality of life and helping society to curb the ?opioid crisis?.